Risk factors for upper urinary tract uroliths and ureteral obstruction in cats under referral veterinary care in the United Kingdom

Abstract Background Cats presenting with upper urinary tract uroliths (UUTUs) and ureteral obstruction (“obstructive UUTU”) are typically younger than cats with idiopathic CKD that often have incidental nephroliths. Hypothesis Cats with upper urinary tract urolith have 2 clinical phenotypes; a more aggressive phenotype at risk of obstructive UUTU at a young age and a more benign phenotype in older cats, with reduced risk of obstructive UUTU. Objectives Identify risk factors for UUTU and for obstructive UUTU. Animals Eleven thousand four hundred thirty‐one cats were referred for care over 10 years; 521 (4.6%) with UUTU. Methods Retrospective VetCompass observational cross‐sectional study. Multivariable logistic regression models were performed to identify risk factors for a diagnosis of UUTU vs no UUTU and additionally, obstructive UUTU vs nonobstructive UUTU. Results Risk factors for UUTU included female sex (odds ratio [OR] 1.6, confidence interval [CI] 1.3‐1.9; P < .001), British shorthair, Burmese, Persian, Ragdoll or Tonkinese (vs non‐purebred ORs 1.92‐3.31; P < .001) breed and being ≥4 years (ORs 2.1‐3.9; P < .001). Risk factors for obstructive UUTU were female sex (OR 1.8, CI 1.2‐2.6; P = .002), having bilateral uroliths (OR 2.0, CI 1.4‐2.9; P = .002) and age, with the odds of obstructive UUTU increasing as age at diagnosis of UUTU decreased (≥12 years, reference category; 8‐11.9 years, OR 2.7, CI 1.6‐4.5; 4‐7.9 years, OR 4.1, CI 2.5‐7.0; 0‐3.9 years, OR 4.3, CI 2.2‐8.6; P < 0.001). Conclusions and Clinical Importance Cats diagnosed with UUTU at a younger age have a more aggressive phenotype with higher risk of obstructive UUTU compared to cats over 12 years of age diagnosed with UUTU.


| INTRODUCTION
Upper urinary tract uroliths (UUTU), affecting the kidney or ureter, can result in ureteral obstruction and acute kidney injury (AKI). Current guidelines advise placing a subcutaneous ureteral bypass (SUB) device or a ureteral stent to manage ureteral obstruction in cats, 1 due to low success rates with medical management. 2 Ureterolithiasis is the most common cause of ureteral obstruction in cats, recorded in 82% of obstructed ureters, 3 or 96% of cats with ureteral obstruction undergoing SUB placement. 4,5 The frequency of UUTU increased 10-fold, up to 68 per 10 000 cats, between 1981 and 2000 in 9 US veterinary teaching hospitals, 6 and anecdotally this prevalence has continued to rise.
The majority of UUTU in cats are calcium oxalate (CaOx). 7,8 The preponderance of data on risk factors associated with CaOx urolith formation in cats stems from submissions to urolith analysis laboratories, but most submitted uroliths are from the lower urinary tract. [9][10][11][12][13][14][15][16] A contributory factor to this is that placement of a SUB does not require ureterolith removal and performing concurrent ureterotomy does not convey any recognized advantage to the cat. 17 Factors associated with all-cause ureteral obstruction, 18 ureteral obstruction due to ureterolithiasis, 8 and the presence of UUTU in cats with chronic kidney disease (CKD) are reported, 19,20 but an epidemiological study of all cats with UUTU is warranted.
Although all UUTU originate in the kidney, not all nephroliths migrate into the ureter. Risk factors for urolith migration in cats are underexplored and it is possible that cats at risk for ureterolithiasis and ureteral obstruction differ from cats with nonmigratory nephroliths. Fourteen cats with mean age 11.6 years, International Renal Interest Society (IRIS) stage 2-3 CKD and concurrent nephrolithiasis did not develop subsequent ureteral obstruction, 21 whereas this has been documented frequently in younger cats. The median age of 163 cats with ureteral obstruction due to ureterolithiasis was 7 years, with a wide age range from 8 months to 16 years. 8 Additionally, 73% of cats diagnosed with CKD in a Japanese referral hospital had concurrent UUTU, with a median age of 5.6 years for the cats with urolithiasis, the majority of which (80%) had ureteroliths at the time of examination. 19 These studies suggest a disparity in age between cats presenting with ureterolithiasis and cats with incidental nephroliths.
We hypothesized that 2 clinical phenotypes exist for cats with UUTU; a more aggressive phenotype at risk of ureteral obstruction at a young age and a more benign phenotype seen in older cats, with a lower risk of obstruction. The objectives of this study were first, to identify all cats diagnosed with UUTU over a 10-year period at a UK tertiary referral hospital and to identify risk factors associated with a diagnosis of UUTU. The second objective was to identify risk factors for ureteral obstruction secondary to ureterolithiasis within those cats with UUTU.

| MATERIALS AND METHODS
An observational cross-sectional study design was used to identify the prevalence and risk factors associated with a diagnosis of UUTU within a cohort of cats seen at a UK veterinary referral hospital.
Power calculations estimated 7626 cats were required to estimate prevalence for UUTU if occurring in 0.6% of cats with 0.1% acceptable margin of error at a 95% confidence level. 22  A diagnosis of ureteral obstruction relied on statements to this effect made by board-certified diagnostic imaging specialists in the case records and included cats considered to have partial or complete obstruction. "Big kidney little kidney" syndrome was defined as a difference in longitudinal kidney measurements on imaging of >0.7 cm between the contralateral kidneys. 24 For UUTU cases, age was recorded at the baseline visit (when first diagnosed) and for non-cases, age was recorded on the final visit date to the QMHA before or on 1 January 2019, whichever came first to allow as much time as possible to be diagnosed with UUTU before classification as a non-case. Neuter status was excluded from analyses because "entire" status was the default option within the hospital's computer software, therefore missing selection of this box during cat data entry might have led to cats being misclassified regarding neuter status. Additionally, the system did not offer an option to record the date of neutering, therefore neuter status at the time of UUTU diagnosis could not be confirmed.
Statistical analysis was performed using R (R Â64 4.1.2). Categorical data were reported as proportions. Continuous data were assessed for normality using histograms, Q-Q plots, and the Shapiro Wilk test.
Data were reported as median (interquartile range [IQR]) or mean (±SD) as appropriate. Comparisons between groups were made using t tests or Wilcoxon rank sum tests for continuous, and chi-squared analyses for categorical data. Two multivariable logistic regression models were built to identify independent risk factors after accounting for the effects of other variables. The first model identified risk factors associated with a diagnosis of UUTU by examining the association of signalment variables (sex, breed, and age) with being a UUTU case (outcome 1) or non-case (outcome 0). Breed descriptive information was cleaned and mapped to a VetCompass breed list derived and extended from the VeNom Coding breed list. 25 The breed type variable included (i) individual breeds with a minimum of 3 UUTU cases or 100 non-cases in the overall study sample, (ii) a grouped category for all non-purebred cats (domestic shorthair, domestic mediumhair, domestic longhair, and cases stated to be crossbred without a specified breed), and (iii) a grouped category for all other purebred and purebred-crosses. Continuous variables were assessed for linearity against the dependent variable and were converted into categorical variables if found to be nonlinearly associated. In consequence, age was categorized as 4 categories: 0-3.9 years, 4.0-7.9 years, 8.0-11.9 years, and ≥12 years.
The second logistic regression model identified risk factors associated with ureteral obstruction due to calcium-based ureterolithiasis.
Cats with ureteroliths known or suspected not to be calcium-based (eg, due to confirmation of a different urolith composition on analysis at any timepoint or due to a diagnosis of a congenital portosystemic shunt) were excluded from this analysis. Cats documented to have ureteral obstruction due to causes other than ureterolithiasis were also excluded. Cats suspected to have calcium-based UUTU were categorized into 2 groups: (i) cats documented to have ureterolithiasis and a partial or complete ureteral obstruction at any timepoint were categorized as "obstructive UUTU" (outcome 1) or (ii) cats never documented to have ureteral obstruction were categorized as "nonobstructive UUTU" (outcome 0). Variables assessed for association with obstructive UUTU were those not directly influenced by the presence of ureteral obstruction (sex, age, bodyweight, purebred vs non-purebred, previous CKD diagnosis, fed dry food only vs mixed or wet food, indoor/outdoor vs indoor only, bilateral vs unilateral uroliths). Age was included as a categorical variable with 4 categories: 0-3.9 years, 4.0-7.9 years, 8.0-11.9 years, and ≥12 years.
For both logistic regression models, variables significant at P < .2 in univariable analyses were carried forwards into backwards, stepwise multivariable logistic regression model-building. A category termed "not reported" was created to allow inclusion within variables with data missing for >10 individuals in the multivariable models.

| RESULTS
The total cohort seen at least once as referral cases at the QMHA between 1 January 2009 and 1 January 2019 included 11 431 cats.
From the total cohort of 11 431, 912 cats were identified as candidate cases and 521 were confirmed to have UUTU, therefore, the overall prevalence of UUTU diagnosis during the 10-year period was 4.6% (95% CI 4.2-5.0). The prevalence of nephrolithiasis was 3.8% (95% CI 3.5-4.2) and the prevalence of ureterolithiasis was 2.4% (95%

| Risk factors associated with a diagnosis of UUTU
Upper urinary tract urolith cases were older than non-cases (median 8.0 [IQR 5.3-11.3] years vs 7.4 [3.2-11.9] years; P < .001) and were more likely to be female (54.1% female vs non-cases 43.4% female; P < .001). Signalment data for the 521 UUTU cases and 10 910 noncases are summarized in Table 1. Multivariable logistic regression identified 3 independent risk factors associated with diagnosis of UUTU: being female, being over 4 years of age and being 1 of 5 specific pure-breeds when compared to non-purebred cats: Ragdoll, Tonkinese, Persian, British shorthair, and Burmese. The Norwegian Forest was at reduced risk of UUTU compared to non-purebred cats (OR 0.11, 95% CI 0.01-0.47). The age category with the highest odds of a diagnosis of UUTU was 4-7.9 years (OR 3.9, 95% CI 2.94-5.25) when compared to the baseline category of <4 years (see Table 2).

| Historical data for cases diagnosed with UUTU
Data regarding diagnoses made before referral, medications administered before referral, diet being fed at the time of referral, cat lifestyle, and presenting clinical signs are detailed in Table 3. Eighty-eight (16.9%) of UUTU cases had a previous diagnosis of CKD. In 19/88 (21.6%), CKD was documented to precede the diagnosis of uroliths, in 25/88 (28.4%) uroliths were documented to precede the diagnosis of CKD, and it was unclear in the records which came first in 44/88 (50.0%) cats. Of note, 3 cases had been diagnosed with a congenital portosystemic shunt and 1 cat had a history of hypervitaminosis D.
Pyrexia (rectal temperature >39.5 C) was noted in 8 (1.5%) cats, and 8 (1.5%) cats were dehydrated on examination. Bodyweight, body condition score (BCS), blood pressure, and other baseline clinicopathologic data for all UUTU cases are reported in Table 4.  women. 29,30 An important difference when comparing these species is that the majority of cats are neutered, therefore the protective effect of estrogen on nephrolith formation seen in women will not apply, 31 however, this is insufficient to explain the disparity in risk of ureteral obstruction between neutered female and male cats. One potential theory is the difference in bodyweight (and therefore size) between female and male cats, with both mixed-breed and purebred female cats frequently demonstrating mean adult bodyweights that are 0.7 to >1.0 kg lower than their male counterparts. 32,33 In the present study, the median bodyweight for female UUTU cases was significantly lower (by just over 1 kg) than for the male UUTU cases and bodyweight was a significant risk factor for obstructive UUTU in univariable analyses, but did not remain in the multivariable model, possibly due to the association between sex and bodyweight. Further work is required to confirm if a smaller bodyweight/size and therefore potentially narrower ureters could increase the risk for urolithiasisassociated ureteral obstruction in female cats.
Our data support the study hypothesis that there are 2 clinical phenotypes of cats that have upper urinary tract urolithiasis; a more aggressive phenotype at risk of ureteral obstruction at a younger age and a more benign phenotype seen in older cats, with a lower risk of ureteral obstruction. Cats that developed obstructive UUTU were significantly younger (median 7.0 years) than cats with nonobstructive uroliths (median 10.0 years). Additionally, age was an independent risk factor for obstructive UUTU, with the odds of a cat developing ureteral obstruction increasing as the age at UUTU diagnosis decreased.
Cats diagnosed with UUTU at 0-3.9 or 4-7.9 years of age had more than 4 times the odds for a diagnosis of obstructive UUTU compared to cats over 12 years of age. Having upper urinary uroliths bilaterally was also an independent risk factor for obstructive UUTU, suggesting that cats with a higher propensity to form nephroliths are also at higher risk for migration of nephroliths into their ureters, in accordance with the hypothesis of a more aggressive phenotype in younger cats. Interestingly, a higher proportion of cats with obstructive UUTU were exclusively fed dry food, which is a risk factor for development of UUTU in cats with CKD, 19 and is a risk factor for ureteral obstruction (all causes) in cats, 18 however, this was not found to be an independent risk factor for obstructive UUTU in the multivariable model.